It is increasingly apparent that Schwann cells (SCs) in the peripheral nervous system (PNS) function as a unit with neurons to regulate sensory function. When the PNS is injured, SCs become activated for repair. This involves dramatic SC phenotypic transformation. If this process is abnormal or inhibited, peripheral nerve in- jury may result in chronic debilitating pain, a problem observed in the general population, including numerous Veterans. Treatment options for chronic neuropathic pain are limited. Unlike many other investigators in the SC field, we hypothesize that in response to injury, SC activation is variable from cell to cell so that a con- tinuum of SC activation states co-exist. We also hypothesize that the SC Repair Program may be augmented therapeutically to improve outcomes. The major goal of this research project is to determine whether we can target SC LDL Receptor-related Protein-1 (LRP1), a receptor that we have identified as playing a central role in SC activation, to improve pain outcomes following peripheral nerve injury. To accomplish our goals, three spe- cific aims are proposed. In Specific Aim 1, we will apply advanced transcriptome profiling technology and a now ?in hand? SC-specific RiboTag mouse model to test the hypothesis that SC activation occurs in a series of steps and may be augmented therapeutically. Central to this Aim is our discovery that specific LRP1 ligands are capable of further activating key cell-signaling pathways that are essential to the SC Repair Program. We hypothesize that these ligands may be candidates for improving outcomes following PNS injury. In Specific Aim 2, our goal is to discover novel LRP1 ligands that are naturally present in the sciatic nerve, mainly after injury, and thus may contribute to activation of the SC Repair Program. This discovery-based Aim applies established capture technology and LC-MS/MS. We have already begun to identify novel ligands in the injured nerve, including Pacsin1 and Decorin, which will be analyzed in validation experiments. Our continuing work should reveal additional ligands that also will be validated using in vitro bioassays to determine optimal can- didates to transition into translational studies. In Specific Aim 3, we will test whether LRP1 ligands with optimal properties (as determined in Specific Aim 2) improve outcomes following PNS injury in mice, as deter- mined by measuring evoked and spontaneous pain. Two categories of LRP1 ligands will be studied. First, LRP1 ligands identified in injured nerves, which may serve as endogenous SC LRP1 activators, will be studied. Second, we propose to examine known LRP1 ligands that have been genetically engineered to capture advantageous activities while eliminating disadvantageous off-target effects. The experiments proposed in Aim 3 are justified by published studies showing that when LRP1 is deleted in SCs in mice, pain-related behaviors increase and by studies in wild-type mice showing that SC LRP1 activity may be augmented in vivo. We consider this project innovative because we target SCs, instead of neurons to treat chronic pain. This work is translational in that it has excellent opportunity to improve management of chronic pain for our VA patients.